| 1. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 2. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 3. |
- Mullins, Niamh, et al.
(författare)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
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Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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| 4. |
- Baker, Jessica H., et al.
(författare)
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Associations Between Alcohol Involvement and Drive for Thinness and Body Dissatisfaction in Adolescent Twins : A Bivariate Twin Study
- 2018
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Ingår i: Alcoholism. - : Wiley-Blackwell. - 0145-6008 .- 1530-0277. ; 42:11, s. 2214-2223
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alcohol involvement has familial associations with bulimic symptoms (i.e., binge eating, inappropriate compensatory behaviors), with several studies indicating a genetic overlap between the two. It is unclear whether overlapping familial risk with alcohol involvement extends to other eating disorder symptoms. Understanding the genetic overlap between alcohol involvement and other eating disorder symptoms may aid in more targeted interventions for comorbid alcohol use-eating disorder symptoms. Thus, we investigated associations between alcohol involvement and 2 core eating disorder symptoms: drive for thinness and body dissatisfaction in adolescent female and male twins.METHODS: We assessed 3 levels of alcohol involvement: alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency via self-report. The Eating Disorder Inventory-II assessed drive for thinness and body dissatisfaction. Sex-specific biometrical twin modeling examined the genetic overlap between alcohol involvement and eating disorder symptoms.RESULTS: Phenotypic associations between alcohol involvement, drive for thinness, and body dissatisfaction were significantly greater in girls compared with boys. A majority of the associations between alcohol involvement, drive for thinness, and body dissatisfaction in girls, but not boys, met our threshold for twin modeling (phenotypic r > 0.20). Moderate genetic correlations were observed between the 3 aspects of alcohol involvement and drive for thinness. Moderate genetic correlations were observed between alcohol use and intoxication frequency and body dissatisfaction.CONCLUSIONS: Together with the literature on alcohol involvement and bulimic symptoms, these findings suggest a generalized association between alcohol involvement and eating disorder symptoms in girls, whereas this association may be symptom specific in boys. Genetic correlations indicate that the amount and direction of this genetic overlap differs across specific symptoms. When intervening on comorbid alcohol involvement and eating disorder symptoms, it may be important to target-specific eating disorder symptoms.
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| 5. |
- Baker, Jessica H., et al.
(författare)
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Illicit Drug Use, Cigarette Smoking, and Eating Disorder Symptoms : Associations in an Adolescent Twin Sample
- 2018
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Ingår i: Journal of Studies on Alcohol and Drugs. - : Alcohol Research Documentation. - 1937-1888 .- 1938-4114. ; 79:5, s. 720-724
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Twin studies have shown that genetic factors in part explain the established relation between alcohol use (i.e., problematic use or abuse/dependence) and eating disorder symptoms in adolescent and adult females. However, studies have yet to elucidate if there are similar shared genetic factors between other aspects of substance involvement, such as illicit drug use and repeated cigarette smoking.Method: For those sex-specific phenotypic correlations above our threshold of.20, we used a behavioral genetic design to examine potential shared genetic overlap between self-reported lifetime illicit drug use and repeated cigarette smoking and the eating disorder symptoms of drive for thinness (DT), bulimia (BU), and body dissatisfaction (BD), as assessed with the Eating Disorder Inventory-II in 16- to 17-year-old female and male twin pairs.Results: Only phenotypic correlations with illicit drug use met our threshold for twin modeling. Small to moderate genetic correlations were observed between illicit drug use and BU in both girls and boys and between illicit drug use and in girls.Conclusions: Similar etiological factors are at play in the overlap between illicit drug use and certain eating disorder symptoms in girls and boys during adolescence, such that genetic factors are important for covariance. Specifically, illicit drug use was associated with bulimia nervosa symptoms in girls and boys, which parallels previous substance use research finding a genetic overlap between alcohol use and bulimia nervosa symptoms. Future research should prospectively examine developmental trajectories to further understand the etiological overlap between substance involvement and eating disorder symptoms.
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| 6. |
- Baker, Jessica H., et al.
(författare)
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Shared Familial Risk Between Bulimic Symptoms and Alcohol Involvement During Adolescence
- 2017
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Ingår i: Journal of Abnormal Psychology. - : American Psychological Association. - 0021-843X .- 1939-1846. ; 126:5, s. 506-518
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Tidskriftsartikel (refereegranskat)abstract
- Twin studies show the established relation between bulimic symptoms and problematic alcohol involvement in adult females is partly due to shared familial factors, specifically shared genetic effects. However, it is unclear if similar shared etiological factors exist during adolescence or in males. We examined the familial overlap (i.e., genetic and common environmental correlations) between bulimic symptoms and various levels of alcohol involvement in 16- to 17-year-old female and male same-sex twin pairs using sex-specific biometrical twin modeling. Bulimic symptoms were assessed with the Eating Disorder Inventory-2. Alcohol involvement included alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency. Results revealed 3 distinct patterns. First, in general, phenotypic correlations indicated statistically similar associations between bulimic symptoms and alcohol involvement in girls and boys. Second, common environmental overlap was significant for the bivariate associations including having ever been intoxicated. Third, moderate genetic correlations were observed between all bulimic symptoms and alcohol involvement in girls and moderate common environmental correlations were observed in boys for the more risky/deviant levels of involvement. Similar to adults, there is familial overlap between bulimic symptoms and alcohol involvement in adolescent girls and boys. These results could inform symptom-and sex-specific, developmentally targeted prevention and intervention programs for the comorbidity between bulimic symptoms and alcohol involvement.
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| 7. |
- Drislane, Laura E., et al.
(författare)
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A triarchic model analysis of the youth psychopathic traits inventory
- 2015
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Ingår i: Journal of Personality Disorders. - : Guilford Publications. - 0885-579X .- 1943-2763. ; 29:1, s. 15-41
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Tidskriftsartikel (refereegranskat)abstract
- The Triarchic model of psychopathy characterizes this complex condition in terms of distinct phenotypic constructs of boldness, meanness, and disinhibition. The current study evaluated the coverage of these constructs provided by a well-established inventory for assessing psychopathy in adolescents, the Youth Psychopathic Traits Inventory (YPI). A consensus rating approach was used to identify YPI items relevant to each Triarchic model construct, and convergent and discriminant validity of the resulting YPI-Triarchic scales were examined in relation to criterion measures consisting of scores on other psychopathy measures and relevant personality trait variables (N = 618, M age = 18.8). The YPI-Triarchic scales showed good internal consistency and exhibited properties largely consistent with predictions based on the Triarchic model, aside from somewhat greater than expected covariance between boldness and other facet scales. Findings are discussed in terms of their implications for interpreting scores on the YPI and for investigating distinctive components of psychopathy in youth.
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| 8. |
- Edwards, Alexis C., et al.
(författare)
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Early environmental influences contribute to covariation between internalizing symptoms and alcohol intoxication frequency across adolescence
- 2011
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Ingår i: Addictive Behaviours. - Oxford, United Kingdom : Elsevier. - 0306-4603 .- 1873-6327. ; 36:3, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- The association between alcohol use and internalizing symptoms during adolescence varies across studies, and the causes underlying this association remain unclear. The current study examines the relationship between symptoms of anxiety and depression and intoxication frequency in a sample of Swedish twins assessed longitudinally from ages 13-14 to 19-20. The objectives of the study were to assess the stability of genetic and environmental influences on each trait across adolescence; to investigate whether these traits share genetic and/or environmental liabilities; and to explore quantitative changes in the shared liability over time. We found that the magnitude of genetic influences on internalizing symptoms remained relatively stable across adolescence, while their impact on intoxication frequency was dynamic. Symptoms of anxiety and depression were influenced by unique environmental factors, while both shared and unique environmental factors influenced intoxication frequency. Genetic and environmental innovation and attenuation were observed for both traits. While no significant genetic correlation was observed between traits, unique environmental factors did contribute to a shared liability. This environmental correlation was positive and moderate (r(E)=0.41) in the early assessment, but decreased and changed direction at later waves (r(E)=-.04 to -.01). The genetic and environmental factors underlying internalizing symptoms and intoxication frequency appear to be developmentally dynamic. Early environmental factors contribute to the association between these traits, but this shared liability diminishes across adolescence.
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| 9. |
- Hettema, John M, et al.
(författare)
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A twin study of the genetics of fear conditioning.
- 2003
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Ingår i: Arch Gen Psychiatry. - : American Medical Association (AMA). - 0003-990X. ; 60:7, s. 702-8
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Tidskriftsartikel (refereegranskat)abstract
- Fear conditioning is a traditional model for the acquisition of fears and phobias. Studies of the genetic architecture of fear conditioning may inform gene-finding strategies for anxiety disorders. The objective of this study was to determine the genetic and environmental sources of individual differences in fear conditioning by means of a twin sample. METHODS: Classic fear conditioning data were experimentally obtained from 173 same-sex twin pairs (90 monozygotic and 83 dizygotic). Sequences of evolutionary fear-relevant (snakes and spiders) and fear-irrelevant (circles and triangles) pictorial stimuli served as conditioned stimuli paired with a mild electric shock serving as the unconditioned stimulus. The outcome measure was the electrodermal skin conductance response. We applied structural equation modeling methods to the 3 conditioning phases of habituation, acquisition, and extinction to determine the extent to which genetic and environmental factors underlie individual variation in associative and nonassociative learning. RESULTS: All components of the fear conditioning process in humans demonstrated moderate heritability, in the range of 35% to 45%. Best-fitting multivariate models suggest that 2 sets of genes may underlie the trait of fear conditioning: one that most strongly affects nonassociative processes of habituation that also is shared with acquisition and extinction, and a second that appears related to associative fear conditioning processes. In addition, these data provide tentative evidence of differences in heritability based on the fear relevance of the stimuli. CONCLUSION: Genes represent a significant source of individual variation in the habituation, acquisition, and extinction of fears, and genetic effects specific to fear conditioning are involved.
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| 10. |
- Hettema, John M., et al.
(författare)
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The genetic covariation between fear conditioning and self-report fears
- 2008
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 63:6, s. 587-593
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fear conditioning is a traditional model for the acquisition of phobias, whereas behavioral therapies use processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. Although prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. Methods: We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. With multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. Results: Phenotypic correlations between experimental and self-report fear measures were modest and, counter-intuitively, negative (i.e., subjects who reported themselves as more fearful had smaller electrophysiologic responses). Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. Conclusions: Experimentally derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders.
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